Glutamic acid is a neurotransmitter that mediates excitation transmission in the central nervous system. In addition to having various functions for neurotransmission, glutamic acid participates in many other important brain functions such as life and death, and differentiation and propagation of neurocytes, development of neurocytes and gliacytes, and plastic change in neurotransmission efficiency of matured or developed brains (Annu. Rev. Biophys. Biomol. Struct., S. Nakanishi, M. Masu, Vol. 23, pp. 319–348, 1994).
Through pharmaceutical and molecular-biological studies, the glutamic acid receptor in the central nervous system of mammals is grouped into two, an ion channel-type glutamic acid receptor and a metabotropic glutamic acid receptor. The ion channel-type glutamic acid receptor comprises a complex of different subunit proteins, and it is an ion channel that is made and broken through ligand bonding. On the other hand, the metabotropic glutamic acid receptor conjugates with GTP-binding protein, and it acts through intracellular second messenger production or ion channel activity control via GTP-binding protein (Brain Res. Rev., S. Nakanishi et al., Vol. 26, pp. 230–235, 1998).
In previous studies, it is reported that metabotropic glutamic acid receptor includes eight different subtypes of metabotropic glutamic acid receptors 1 to 8. These are grouped into three subgroups, depending on their amino acid sequence homology, signal transmission and pharmaceutical properties. Regarding their function for intracellular signal transmission, those of group I (metabotropic glutamic acid receptors 1 and 5) activate phospholipase C, and those of group II (metabotropic glutamic acid receptors 2 and 3) and group III (metabotropic glutamic acid receptors 4, 6, 7 and 8) act for adenylate cyclase activity control to thereby retard cyclic adenosine monophosphate (cAMP) accumulation through forskolin stimulation. Those of group II are selectively activated by LY354740 described in Journal of Medicinal Chemistry, Vol. 42, pp. 1027–1040, 1999; andthoseof group III are by L-AP4. Except metabotropic glutamic acid receptor 6 that specifically exists in the retina, the other receptors are expressed broadly in brain and nervous systems, each showing characteristic intracerabral distribution therein, and it is believed that these receptors individually play their own different physiological roles (Neurochem. Int., D. Shoepp et al., Vol. 24, pp. 439–449, 1994; Eur. J. Pharmacol., J. Pin et al., Vol. 375, pp. 277–294, 1999).
Other various publications mentioned below suggest the usefulness of metabotropic glutamic acid receptor antagonist.
1. Neuroscience, Vol. 19, pp. 955–963, 1999 says that any behavioral change is not seen in metabotropic glutamic acid receptor 7 knockout mice based on the anxiety caused by electric stimulation or other unpleasant stimulation by LiCl.
2. Eur. J. Pharmacol., Vol. 319. , pp. 153–156, 1997 says that, when an antagonist to group III metabotropic glutamic acid receptors, α-methylserine-O-phosphate (MSOP) is administered to the hippocampus of rats, then it relaxes the conflict condition of rats and acts for antianxiety for them.
3. Behavioural Brain Res., Vol. 81, pp. 69–79, 1996 says that the learning disability caused by L-AP4 induction is inhibited by an antagonist to metabotropic glutamic acid receptor, MAP4.
4. Neuropharmacol., Vol. 34, pp. 991–1001, 1995 says that the long-term enhancing phenomenon of synaptic conduction efficiency that is seen in the hippocampus is inhibited by the above-mentioned L-AP4.
5. Neuroreport, Vol. 7, pp. 1469–1474, 1996 says that the above-mentioned L-AP4 has an effect of inducing convulsion.
6. Neuropharmacol., Vol. 38, pp. 1631–1640, 1999 says that, when the above-mentioned L-AP4 is applied to striate body-cultured neurocytes, then it induces death of neurocytes.
7. The Journal of Pharmacology and Experimental Therapeutics (JPET), Vol. 292, pp. 406–414, 2000 says that the above-mentioned L-AP4 administered to lateral nuclei of medulla oblongata increases the level of horizontal motion.
8. Pain, Vol. 85, pp. 183–189, 2000 says that a metabotropic glutamic acid receptor agonist, L-SOP administered to the gray matter in the cerebral aqueduct enhances the algesiogenic reaction owing to formalin administration and the enhancing reaction is blocked by the above-mentioned MSOP.
From the above-mentioned descriptions, metabotropic glutamic acid receptor antagonists are useful for medicines, for example, for various mental disorders such as anxiety disorders, psychosomatic disorders, obsessive-compulsive neurosis, bipolar disorders, melancholia, eating disorders, schizophrenia, epilepsy; various types of dementia or attention/cognition deficit disorders such as Alzheimer disease, multi-infarct dementia; retrograde dyskinesia such as Parkinson disease, Huntington's chorea, amyotrophic lateral sclerosis; neurological disorders or neuropathy owing to, for example, cerebral infarction, transient ischemic attack, or wound in the head; and acute or persistent pain in cancer, etc.
Isoxazolopyridone skeleton-having compounds that have structural relation to the compounds of the invention are described in, for example, JP-A 51-113877 (hereinafter referred to as reference A) and JP-A 52-19675 (hereinafter referred to as reference B). Reference A says that isoxazolopyridone derivatives have a blood lipid depressing effect. Reference B illustrates isoxazolopyridone derivatives as intermediates for medicines. However, references A and B do neither say nor suggest that isoxazolopyridone derivatives might have a function as antagonist and/or agonist for metabotropic glutamic acid receptors.